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Effect of dietary CuR beginning at 4 or 5 wk of age on CuD-induced body weight change in mice. CuR4, repletion starting at wk 4; CuR5, repletion starting at wk 5. Values are means SEM, n 3-10. Means without a common letter differ, P 0.05.
Source publication
Dietary copper deficiency (CuD)(3) leads to cardiac hypertrophy in various animal models. We showed recently that heart failure develops after hypertrophy in FVB mice fed a CuD diet. The present study was undertaken to determine whether CuD-induced cardiac failure is reversible upon copper repletion (CuR). Dams of FVB mice were fed a CuD diet (0.3...
Context in source publication
Context 1
... etary copper deficiency caused body weight loss starting from 5 wk of age ( Fig. 1). By 6 wk, CuD mice were lethargic and died soon after. Reintroduction of the CuA diet to CuD mice at 5 wk of age resulted in a regain of the lost body weight. When the CuA diet was reintroduced at 4 wk of age, the body weight gain of the mice did not differ from that of the control mice fed CuA diet continuously, i.e., the CuA and ...
Citations
... The mechanism involved include: (1) copper deficiency is associated with impaired endothelium dependent responses to acetylcholine and histamine in the rat thoracic aorta [113]; (2) copper deficiency inhibits the nitric oxidemediated mechanism of vascular smooth muscle relaxation [114]. Dietary copper deficiency caused lipid deposition in the myocardium, and blunted myocardial responses to the beta-adrenergic agonist, isoproterenol, aggravated heart failure [115]. Then, copper supplementation could reverse hypertrophic cardiomyopathy induced by chronic pressure overload in mice [116]. ...
Ischemic vascular diseases are on the rise globally, including ischemic heart diseases, ischemic cerebrovascular diseases, and ischemic peripheral arterial diseases, posing a significant threat to life. Copper is an essential element in various biological processes, copper deficiency can reduce blood vessel elasticity and increase platelet aggregation, thereby increasing the risk of ischemic vascular disease; however, excess copper ions can lead to cytotoxicity, trigger cell death, and ultimately result in vascular injury through several signaling pathways. Herein, we review the role of cuproptosis and copper deficiency implicated in ischemic injury and repair including myocardial, cerebral, and limb ischemia. We conclude with a perspective on the therapeutic opportunities and future challenges of copper biology in understanding the pathogenesis of ischemic vascular disease states.
... Supplementation by a Cu-adequate diet has been shown to reverse cardiac hypertrophy in subjects with dietary Cu deficiency (10) and in patients with hypertrophic cardiomyopathy (HCM) carrying mutations in Cu chaperones, SCO1 and SCO2 (11). Moreover, Cu repletion reversed the HCM phenotype in Cu-deficient and pressure overload animal models via SOD-mediated HIF-1 activation of VEGF (vascular endothelial growth factor) expression and angiogenesis (10)(11)(12)(13). Disturbed Cu metabolism has also been connected to ischemic heart disease and heart failure involving dysfunction of CP, SOD1, and SOD3 chaperones (11). ...
... Interestingly, Cu repletion recovered MMP2 level and reduced cardiac fibrosis in a rat model of pressure overload-induced cardiac hypertrophy (56). It has been shown that Cu could also increase Zn concentration in the heart, along with upregulation of MMP2 (12,57), indicating that the balanced Cu content and MMP2 are important for cardiac morphology and function. The other genes noteworthy to mention are Ctsa and Armcx1. ...
Background:
Copper (Cu) is essential for the functioning of various enzymes involved in important cellular and physiological processes. Although critical for normal cardiac function, excessive accumulation, or deficiency of Cu in the myocardium is detrimental to the heart. Fluctuations in cardiac Cu content have been shown to cause cardiac pathologies and imbalance in systemic Cu metabolism. However, the genetic basis underlying cardiac Cu levels and their effects on heart traits remain to be understood. Representing the largest murine genetic reference population, BXD strains have been widely used to explore genotype-phenotype associations and identify quantitative trait loci (QTL) and candidate genes.
Methods:
Cardiac Cu concentration and heart function in BXD strains were measured, followed by QTL mapping. The candidate genes modulating Cu homeostasis in mice hearts were identified using a multi-criteria scoring/filtering approach.
Results:
Significant correlations were identified between cardiac Cu concentration and left ventricular (LV) internal diameter and volumes at end-diastole and end-systole, demonstrating that the BXDs with higher cardiac Cu levels have larger LV chamber. Conversely, cardiac Cu levels negatively correlated with LV posterior wall thickness, suggesting that lower Cu concentration in the heart is associated with LV hypertrophy. Genetic mapping identified six QTLs containing a total of 217 genes, which were further narrowed down to 21 genes that showed a significant association with cardiac Cu content in mice. Among those, Prex1 and Irx3 are the strongest candidates involved in cardiac Cu modulation.
Conclusion:
Cardiac Cu level is significantly correlated with heart chamber size and hypertrophy phenotypes in BXD mice, while being regulated by multiple genes in several QTLs. Prex1 and Irx3 may be involved in modulating Cu metabolism and its downstream effects and warrant further experimental and functional validations.
... Capillary density decreases with the loss of Cu, and a failing heart's myocardial mitochondria's structure and function are altered (11,12). In hypertrophic hearts instigated by contraction of the upper aorta and dietary Copper deficiency, Copper supplementation enhanced the contractile function as well as structural integrity (6,13). In fundamental investigations, several studies have shown a connection between copper depletion and myocardial ischemic infarction (14). ...
Objectives
Most studies have examined the association between serum copper and myocardial infarction, but there is little evidence of the association between dietary copper intake and myocardial infarction.
Materials and methods
The study included a total of 14,876 participants from the 2011 to 2018 National Health and Nutrition Examination Survey (NHANES). Multivariate logistic regression model was used to analyze the association between dietary copper intake and the risk of myocardial infarction. To reduce selection bias, we use nearest neighbor propensity score matching (PSM) in a 1:2 ratio. Restricted cubic spline (RCS) method is used to study the non-linear relationship. Subgroup stratification was used to further investigate the association between copper intake and myocardial infarction.
Results
The median dietary copper intake was 1.0825 mg/day. A myocardial infarction had occurred in approximately 4.4% (655) of the participants. Before and after matching, multivariate logistic regression models revealed a negative correlation between dietary copper intake and the risk of myocardial infarction. The higher quartile of subjects had a noticeably lower risk of myocardial infarction in comparison to those in the first quartile of copper intake. According to RCS findings, dietary copper intake and myocardial infarction have a non-linear and dose-response relationship. According to stratified analysis, the dietary copper intake was a substantial protective element for those who were ≥ 50 years old, female, 25 ≤BMI <30, with history of smoking, hypertension, diabetes and ortholiposis.
Conclusion
Increased dietary copper intake was associated with a lower risk of myocardial infarction. It is especially significant in elderly-aged women, overweight individuals, smokers, hypertension, and diabetic patients.
... 227 In Cu-deficient mice, lipids are deposited in the myocardial tissue, with cardiac hypertrophy, mitochondrial swelling, and a blunted response to the isoproterenol, an agonist of beta-adrenergic; The repletion of Cu could reverse these changes in the heart and improve electrical conduction. 229,230 Interestingly, in a patient with SCO2 mutations who presented with severe hypertrophic cardiomyopathy, Cuhistidine supplementation has been reported to improve heart function, showing attenuated cardiomyopathy as well as the normalization of blood pressure. 231 Given that altered regulation of Cu, homeostasis has been associated with a variety of disease conditions, future studies are warranted in order to determine the precise mechanism by which Cu imbalance causes cellular damage, thus providing important new information that can be used to design treatments for preventing disease and/or slowing disease progression. ...
As an essential micronutrient, copper is required for a wide range of physiological processes in virtually all cell types. Because the accumulation of intracellular copper can induce oxidative stress and perturbing cellular function, copper homeostasis is tightly regulated. Recent studies identified a novel copper-dependent form of cell death called cuproptosis, which is distinct from all other known pathways underlying cell death. Cuproptosis occurs via copper binding to lipoylated enzymes in the tricarboxylic acid (TCA) cycle, which leads to subsequent protein aggregation, proteotoxic stress, and ultimately cell death. Here, we summarize our current knowledge regarding copper metabolism, copper-related disease, the characteristics of cuproptosis, and the mechanisms that regulate cuproptosis. In addition, we discuss the implications of cuproptosis in the pathogenesis of various disease conditions, including Wilson’s disease, neurodegenerative diseases, and cancer, and we discuss the therapeutic potential of targeting cuproptosis.
... MMP-2 is regulated by hypoxia-inducible factor-1 (HIF-1), which requires copper for its transcriptional activity [72]. Moreover, MMP-2 activity is zinc-dependent: zinc uptake is dependent on copper status [73]. MMP-2 activity is also inversely affected by lysyl oxidase, a copper-dependent enzyme involved in collagen-elastin crosslinking [74]. ...
Abnormality in myocardial copper homeostasis is believed to contribute to the development of cardiomyopathy. Trientine, a copper-chelating drug used in the management of patients with Wilson’s disease, demonstrates beneficial effects in patients with hypertrophic cardiomyopathy. This review aims to present the updated development of the roles of trientine in hypertrophic cardiomyopathy. The drug has been demonstrated in animal studies to restore myocardial intracellular copper content. However, its mechanisms for improving the medical condition remain unclear. Thus, comprehending its mechanistic aspects in cardiomyopathy is crucial and could help to expedite future research.
... After 9 or 15 months of copperrestricted diet feeding, rats show cardiac diastolic and systolic dysfunction, evidenced by a blunted response of +dP/dt, −dP/dt, and LVEDP to isoproterenol [121]. Feeding a copper-adequate diet for 4 weeks to diet-induced copper-deficient mice completely restores cardiac diastolic and systolic function and the response to β-adrenergic stimulation [122], suggesting that the cardiac response to β-adrenergic stimulation requires copper. ...
Copper is an essential trace metal element that significantly affects human physiology and pathology by regulating various important biological processes, including mitochondrial oxidative phosphorylation, iron mobilization, connective tissue crosslinking, antioxidant defense, melanin synthesis, blood clotting, and neuron peptide maturation. Increasing lines of evidence obtained from studies of cell culture, animals, and human genetics have demonstrated that dysregulation of copper metabolism causes heart disease, which is the leading cause of mortality in the US. Defects of copper homeostasis caused by perturbed regulation of copper chaperones or copper transporters or by copper deficiency resulted in various types of heart disease, including cardiac hypertrophy, heart failure, ischemic heart disease, and diabetes mellitus cardiomyopathy. This review aims to provide a timely summary of the effects of defective copper homeostasis on heart disease and discuss potential underlying molecular mechanisms.
... 17 Cu supplementation replenishes cardiac Cu content and improves structural integrity and contractile function in hypertrophic hearts induced not only by dietary Cu deficiency, but also by ascending aortic constriction. 33,34 Clinical and experimental studies have demonstrated the link between myocardial ischemic infarction and Cu depletion. 6,35 It is thus interesting to know if prevention of Cu loss from the heart can suppress myocardial ischemic injury. ...
Copper depletion is associated with myocardial ischemic infarction, in which copper metabolism MURR domain 1 (COMMD1) is increased. The present study was undertaken to test the hypothesis that the elevated COMMD1 is responsible for copper loss from the ischemic myocardium, thus worsening myocardial ischemic injury. Mice (C57BL/6J) were subjected to left anterior descending coronary artery permanent ligation to induce myocardial ischemic infarction. In the ischemic myocardium, copper reduction was associated with a significant increase in the protein level of COMMD1. A tamoxifen-inducible, cardiomyocyte -specific Commd1 knockout mouse (C57BL/6J) model ( COMMD1 CMC▲/▲ ) was generated using the Cre-LoxP recombination system. COMMD1 CMC▲/▲ and wild-type littermates were subjected to the same permanent ligation of left anterior descending coronary artery. At the 7th day after ischemic insult, COMMD1 deficiency suppressed copper loss in the heart, along with preservation of vascular endothelial growth factor and vascular endothelial growth factor receptor 1 expression and the integrity of the vascular system in the ischemic myocardium. Corresponding to this change, infarct size of ischemic heart was reduced and myocardial contractile function was well preserved in COMMD1 CMC▲/▲ mice. These results thus demonstrate that upregulation of COMMD1 is at least partially responsible for copper efflux from the ischemic heart. Cardiomyocyte-specific deletion of COMMD1 helps preserve the availability of copper for angiogenesis, thus suppressing myocardial ischemic dysfunction.
... 14 Cardiac dysfunction in HF could result from LV copper deficiency, since redox-active copper acts as a cofactor for proteins involved in crucial biological reactions including mitochondrial respiration and free radical elimination. Physiological copper levels are necessary for maintaining cardiac structure and function, and even slight copper deficiency can cause serious defects in cardiac copper metabolism, leading to extensive changes in myofibrillar and mitochondrial morphology and distribution that can promote HF. 9,14,15 The heart has a particularly high demand for copper in order to sustain mitochondrial oxidative phosphorylation and generate the large amounts of energy required to support cardiac muscle contraction, peptide hormone biogenesis, oxidative stress protection, and other critical functions. 16,17 Studies have shown that defective copper homeostasis leading to myocardial copper deficiency accompanies cardiovascular damage in diabetic animals and patients. ...
... Diabetes impairs systemic copper homeostasis 7,13,28 and lowers myocardial copper, 14 to levels similar to those found in dietary copper deficiency, 15 but the processes leading to diabetes-evoked myocardial copper deficiency are poorly understood. TETA treatment restores copper homeostasis in diabetic rats and patients, probably by removing excess extracellular Cu(II) bound to N-e-carboxymethyllysine in extracellular proteins, 50 forming a Cu(II)-TETA complex that is excreted via the urine, 7 restoring myocardial copper levels through repairing cytosolic Ctr2 function, 24,51 and rebalancing intra-and extra-cellular copper pools. ...
Diabetes impairs systemic copper regulation, and acts as a major independent risk factor for heart failure (HF) wherein mitochondrial dysfunction is a key pathogenic process. Here we asked whether diabetes might alter mitochondrial structure/function and thus impair cardiac performance by damaging myocellular pathways that mediate cell-copper homeostasis. We measured activity of major mitochondria-resident copper-enzymes cytochrome c oxidase (mt-Cco) and superoxide dismutase 1 (mt-Sod1); expression of three main mitochondrial copper-chaperones [Cco copper chaperone 17 (Cox17), Cox11, and mitochondria-resident copper chaperone for Sod1 (mt-Ccs)]; of copper-dependent Cco-assembly protein Sco1; and regulation of mitochondrial biogenesis in left-ventricular (LV) tissue from groups of non-diabetic-control, untreated-diabetic, and divalent-copper-selective chelator-treated diabetic rats. Diabetes impaired LV pump function; ~halved LV-copper levels; substantively decreased myocellular expression of copper chaperones, and enzymatic activity of mt-Cco and mt-Sod1. Divalent-copper chelation with triethylenetetramine improved cardiac pump function, restored levels of myocardial copper, the copper chaperones, and Sco1; and enzymatic activity of mt-Cco and mt-Sod1. Copper chelation also restored expression of the key mitochondrial biogenesis regulator, peroxisome-proliferator-activated receptor gamma co-activator-1α. This study shows for the first time that altered myocardial copper-trafficking is a key pathogenic process in diabetes-evoked HF. We also describe a novel therapeutic effect of divalent-copper-selective chelation, namely restoration of myocellular copper trafficking, which is thus revealed as a potentially tractable target for novel pharmacological intervention to improve cardiac function.
... 2,9 Dietary copper supplementation reverses cardiac hypertrophy induced by pressure overload. 10 Copper is required for cardiac structure and function, [11][12][13][14][15] and pressure overload-induced cardiac hypertrophy is accompanied by copper depletion in the heart. 10 Thus, it becomes a reasonable and clinically sound approach to improve cardiac structural and functional recovery from pathological hypertrophy by copper supplementation. ...
... 2,9 In our previous studies, we used dietary copper supplementation as a tool to restore copper content in the heart in the mouse model. 10,13 However, we observed, under pressure overload condition, that copper concentrations in the blood were actually elevated, as presented here. Dietary copper supplementation would further increase the elevated level of copper in the blood, which would lead to untoward effects, although these have not been defined. ...
... It was also observed that dietary copper supplementation leads to copper repletion in the heart and regression of cardiac hypertrophy. [10][11][12][13] The mechanism for copper repletion-induced regression of cardiac hypertrophy has been extensively studied. It includes the recovery of VEGF production 10,43 and activation of VEGF receptor-1, not receptor-2, in the hypertrophic heart. ...
Impact statement:
Our study reveals that TETA, traditionally regarded as a copper chelator, in lower doses delivers copper selectively to the heart through a mechanism independent of copper transporter-1 or -2. Copper supplementation by a lower dose of TETA suppresses pressure overload-induced cardiac hypertrophy. Since ischemic heart disease and hypertrophic cardiomyopathy are accompanied by myocardial copper loss, this approach of using a lower dose of TETA to supplement copper to the heart would help treat the disease condition of patients with such cardiac events.
... Copper repletion reversed these changes, indicating that copper deficiency is an appealing target in cardiomyopathy. 58 In a patient with mutations in Sco2, a copper-transport protein that delivers copper to CCO, copper-histidine resolves severe hypertrophic cardiomyopathy. 59 Copper, blood vessels and circulating blood cells Copper deficiency causes an exaggerated response of blood vessels to inflammatory stimuli. ...
